levels in the fasting state. Because insulin secretion is glucose dependent, the risk of hypoglycemia is minimized. Patients with type 2 diabetes have abnormalities associated with the secretion of incretin hormones, causing a deficiency of GLP- 1 and resistance to the action of GIP. The GLP-1 RA class of medications mimics the actions of the endogenous GLP-1 hormone and helps to offset the impairment. The use of GLP-1 Side effects GLP-1 RAs are generally well tolerated. However, the most reported side effects are GI, including nausea, vomiting, and diarrhea (Trujillo, 2022). GI side effects usually occur early in treatment, are transient, and are somewhat mild. In addition, because GLP-1 RAs increase insulin secretion from pancreatic beta cells in a glucose-dependent manner in response to food
RAs also affects the stomach through the autonomic nervous system to slow gastric emptying, thereby reducing meal-related glucose excursions. Finally, GLP-1 RAs cross the blood–brain barrier, thus increasing satiety via the central nervous system (CNS). These actions result in a reduction of glucose and weight (Trujillo, 2022). intake, the risk of hypoglycemia is low. However, when GLP- 1 RAs are combined with sulfonylureas or insulin, the risk of hypoglycemia increases. Occasionally, injection-site reactions occur with long-acting injectable agents. In addition, with exenatide once weekly, there is a risk of nodule formation from using microspheres in long-acting formulations. The 2022 Standards of Medical Care by the American Association of Diabetes (ADA) and the consensus report by the ADA and the European Association for the Study of Diabetes (EASD) recommend the use of GLP-1 RAs combined with metformin when additional therapy is needed to achieve a patient’s A1C glycemic target, when weight management is a key factor, and when patients have atherosclerotic cardiovascular disease (ASCVD) or are at high risk for ASCVD (Davies et al., 2022; ElSayed et al., 2023a). Similarly, GLP-1 RAs are the preferred treatment over basal insulin and are recommended as the first injectable agent. In addition, American Association of Clinical Endocrinologists (AACE) guidelines recommend long-acting GLP-1 RAs or SGLT2 inhibitors if patients have high ASCVD risk, stage 3 chronic kidney disease (CKD), or HF with reduced ejection fraction, independent of glycemic control (Garber et al., 2020).
Dosing of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) The recommended dose for GLP-1 RAs is shown in Table 8. All GLP-1 RAs are available in injectable pens and are administered subcutaneously into the abdomen, thigh, or upper arm. Some pen devices are single use, while others are multiuse. In addition, some injectable pens require needle attachment, while others come with the needle already attached. Dosing schedules for GLP-1 RAs range from twice daily to weekly. After initiating GLP- 1 RAs, starting doses begin lower, followed by titration to higher doses (Trujillo, 2022). Short-acting GLP-1 RAs have specific timing requirements concerning meals because their mechanisms are more targeted toward slowing gastric emptying postprandially. If patients miss a dose of exenatide (Byetta) or lixisenatide (Adlyxin), they should skip it and take it at the next prescribed time. Also, GLP-1 RAs are kept refrigerated until they are used. After the first dose, the GLP-1 RA can be stored at room temperature. Exenatide (Byetta) should be discarded 30 days after the first use, while lixisenatide (Adlyxin) is discarded 14 days after the first use (Trujillo, 2022).
Table 8: Injectable Agents: GLP-1 RAs GLP-1 RAs
Available Strengths
Starting Dose
How to Titrate Dose
Dosage Range
Generic Name (Trade Name)
Exenatide (Byetta)
• Multidose pen (5 ug/ dose or 10 u/dose). • 60 doses per pen. • Single-dose pen (2 mg). • Multidose pen (6 mg/ mL); each pen delivers 0.6 mg, 1.2 mg, or 1.8 mg. • Multidose pen (10 ug/ dose or 20 ug/dose); 14 doses per pen. • Single-dose pen (0.75 mg, 1.5 mg, 3 mg, 4.5 mg).
• Start with 5 u twice daily.
• Increase to 10 u twice daily after one month if patient has not reached A1C target.
• 5–10 ug/twice daily.
Exenatide Extended- Release (Bydureon)
• 2 mg/once
weekly; inject any time of day with or without meals. • Start with 0.6 mg/ once daily for 1 week.
Liraglutide (Victoza)
• Increase to 1.2 mg/once daily and increase to 1.8 mg/once daily if glucose target not reached.
• 0.6–1.8 mg/ once daily.
Lixisenatide (Adlyxin) Dulaglutide (Trulicity)
• Start with 10 ug/ once daily for 14 days.
• Increase to 20 ug/once daily.
• 10–20 ug/ once daily.
• Start with 0.75
• Increase to 1.5 mg/once weekly if patient has not reached glycemic target; may increase to 3 mg/once weekly then 4.5 mg/once weekly if needed. • Increase to 0.5 mg/once weekly after 4 weeks if patient has not reached A1C target; can increase to 1 mg/ once weekly and if glycemic goal not achieved after 4 weeks can increase to 2 mg/once weekly.
• 0.75–4.5 mg/ weekly.
mg/once weekly.
Semaglutide (Ozempic)
• Multidose pen; lower- dose pens deliver 0.25 to 0.5 mg; higher- dose pens deliver 1 to 4 mg/3mL.
• Start with 0.25
• 0.25–2 mg/
mg/once weekly.
once weekly.
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